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Aims: The PARACOR‐19 randomized controlled trial (RCT) was designed to examine the effects of sacubitril/valsartan on markers of cardiac injury, inflammation, structure, and function among patients who have recovered from acute coronavirus disease 2019 (COVID‐19) infection. Methods and results: PARACOR‐19 was a single‐centre, double‐blind RCT of patients with cardiovascular risk factors and a history of COVID‐19 infection 4–16 weeks prior to enrolment. Patients were randomized to sacubitril/valsartan (titrated to the maximum dose of 97/103 mg twice daily) versus matching placebo. Co‐primary endpoints were change from baseline to 12 weeks in high‐sensitivity cardiac troponin T (hs‐cTnT) and soluble ST2 (sST2). Exploratory endpoints included change from baseline to 12 weeks in additional circulating biomarkers. Overall, 42 patients were randomized between August 2021 and March 2023 (n = 20 sacubitril/valsartan, n = 22 placebo). Median (25th–75th) time from COVID‐19 diagnosis to enrolment was 67 (48–80) days. Median age was 67 (62–71) years, 48% were female, and 91% were White. Compared with placebo, sacubitril/valsartan did not have a significant effect on the co‐primary endpoints of change from baseline in hs‐TnT and sST2 (all p ≥ 0.29). In exploratory analyses, sacubitril/valsartan led to a 46% greater reduction in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and 51% greater reduction in C‐terminal telopeptide of collagen type I (CITP). Permanent drug discontinuation occurred in four patients in the sacubitril/valsartan group and three patients in the placebo group. There were no deaths and one patient was hospitalized in each group. Conclusion: In this pilot RCT of patients who recovered from acute COVID‐19, sacubitril/valsartan did not lower hs‐cTnT or sST2 compared with placebo. Exploratory analyses suggested potential benefits of sacubitril/valsartan on cardiac wall stress and collagen turnover as measured by NT‐proBNP and CITP. Sacubitril/valsartan was well tolerated. Clinical Trial Registration: ClinicalTrials.gov NCT04883528. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effects of Cimlanod, a nitroxyl donor with vasodilator properties, on water and salt excretion after an administration of an intravenos bolus of furosemide. Methods and results: In this randomized, double‐blind, mechanistic, crossover trial, 21 patients with left ventricular ejection fraction <45%, increased plasma concentrations of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and receiving loop diuretics were given, on separate study days, either an 8 h intravenous (IV) infusion of cimlanod (12 μg/kg/min) or placebo. Furosemide was given as a 40 mg IV bolus four hours after the start of infusion. The primary endpoint was urine volume in the 4 h after the bolus of furosemide during infusion of cimlanod compared with placebo. Median NT‐proBNP at baseline was 1487 (interquartile range: 847–2665) ng/L. Infusion of cimlanod increased cardiac output and reduced blood pressure without affecting cardiac power index consistent with its vasodilator effects. Urine volume in the 4 h post‐furosemide was lower with cimlanod (1032 ± 393 ml) versus placebo (1481 ± 560 ml) (p = 0.002), as were total sodium excretion (p = 0.004), fractional sodium excretion (p = 0.016), systolic blood pressure (p < 0.001), estimated glomerular filtration rate (p = 0.012), and haemoglobin (p = 0.010), an index of plasma volume expansion. Conclusions: For patients with heart failure and congestion, vasodilatation with agents such as cimlanod reduces the response to diuretic agents, which may offset any benefit from acute reductions in cardiac preload and afterload. [ABSTRACT FROM AUTHOR]

Aims: Serial assessment of natriuretic peptides is widely utilized in heart failure clinics. Uncertainty exists regarding the value of multiple natriuretic peptide measurements and how they might be best interpreted. Methods and results: Six hundred thirty‐two patients with heart failure with reduced ejection fraction (<40%) and complete biomarker data were enrolled to receive sacubitril/valsartan. Patients underwent periodic study visits during 1‐year follow‐ups. Echocardiographic data and cardiac biomarkers, including N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were collected during study visits. Patients were categorized into three groups based on tertiles of baseline NT‐proBNP levels. The area under the curve (AUC) of NT‐proBNP measurements across study visits was calculated. Compared with patients with higher AUC (and thus higher concentrations over a longer period of time), those with lower AUC were younger, had a lower prevalence of chronic kidney disease, prior coronary artery bypass graft, atrial fibrillation, and higher body‐mass index. A significant interaction existed between baseline NT‐proBNP and subsequent AUC for predicting LVEF change across visits (P‐value < 0.001): among those with lower baseline NT‐proBNP, similar improvements in left ventricular (LV) volumes LV ejection fraction, and LV mass index were observed across subsequent AUC (P‐value > 0.1). However, among those with higher baseline NT‐proBNP, those with lower subsequent AUC had a greater improvement in cardiac remodelling indices (P‐value < 0.05). Conclusions: Serial NT‐proBNP monitoring (integrating the totality of measurements as an AUC) during treatment with sacubitril/valsartan informs unique information regarding the future changes in cardiac remodelling indices, especially among those with higher NT‐proBNP levels at baseline. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) guidelines recommend initiation and optimization of guideline‐directed medical therapy, including mineralocorticoid receptor antagonists (MRAs), before hospital discharge. However, scientific evidence for this recommendation is lacking. Our objective was to determine whether initiation of MRA prior to hospital discharge is associated with improved outcomes. Methods and results: We performed a secondary analysis of 6197 patients enrolled in the RELAX‐AHF‐2 study. Patients were divided into four groups according to MRA therapy at baseline and discharge. At baseline 30% of patients received MRA therapy, which increased to 50% of patients at discharge. In‐hospital initiation of an MRA was observed in 1690 (27%) patients, 1438 (23%) patients remained on MRA therapy, 418 (7%) patients discontinued MRA treatment, and 2651 (43%) patients did not receive an MRA during hospital stay. Compared with patients who did not receive MRA therapy, in‐hospital initiation of an MRA was independently associated with lower risks of mortality (multivariable hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.60–0.96; p = 0.02), cardiovascular death (HR 0.77, 95% CI 0.59–1.01; p = 0.06), hospitalization for HF or renal failure (HR 0.72, 95% CI 0.60–0.86; p = 0.0003) and the composite endpoint of cardiovascular death and/or rehospitalization for HF or renal failure (HR 0.71, 95% CI 0.61–0.83; p < 0.0001) at 180 days. These results were independent of baseline left ventricular ejection fraction. Conclusion: In patients hospitalized for acute HF, in‐hospital initiation of an MRA was associated with improved post‐discharge outcomes, independent of left ventricular ejection fraction and other potential confounders. [ABSTRACT FROM AUTHOR]

Aims: Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play a role in beneficial effects of sacubitril/valsartan (Sac/Val) treatment. Methods and results: Mid‐regional pro‐adrenomedullin (MR‐proADM) was measured in 156 patients with heart failure with reduced ejection fraction (HFrEF) treated with Sac/Val and 264 patients with heart failure with preserved ejection fraction (HFpEF) randomized to treatment with Sac/Val or valsartan. Echocardiography and Kansas City Cardiomyopathy Questionnaire results were collected at baseline and after 6 and 12 months in the HFrEF cohort. Median (Q1–Q3) baseline MR‐proADM concentrations were 0.80 (0.59–0.99) nmol/L in HFrEF and 0.88 (0.68–1.20) nmol/L in HFpEF. After 12 weeks of treatment with Sac/Val, MR‐proADM increased by median 49% in HFrEF and 60% in HFpEF, while there were no significant changes in valsartan‐treated patients (median 2%). Greater increases in MR‐proADM were associated with higher Sac/Val doses. Changes in MR‐proADM correlated weakly with changes in N‐terminal pro‐B‐type natriuretic peptide, cardiac troponin T and urinary cyclic guanosine monophosphate. Increases in MR‐proADM were associated with decreases in blood pressure, but not significantly associated with changes in echocardiographic parameters or health status. Conclusions: MR‐proAD concentrations rise substantially following treatment with Sac/Val, in contrast to no change from valsartan. Change in MR‐proADM from neprilysin inhibition did not correlate with improvements in cardiac structure and function or health status. More data are needed regarding the role of adrenomedullin and its related peptides in the treatment of heart failure. Clinical Trial Registration: PROVE‐HF ClinicalTrials.gov Identifier: NCT02887183, PARAMOUNT ClinicalTrials.gov Identifier: NCT00887588. [ABSTRACT FROM AUTHOR]

Natriuretic peptides, brain (B‐type) natriuretic peptide (BNP) and N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor–neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up‐to‐date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptide‐guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions. [ABSTRACT FROM AUTHOR]

Aims: The impact of mitral regurgitation (MR) in patients hospitalized for acute heart failure (AHF) is not well established. We assessed the role of MR in patients enrolled in the Relaxin in Acute Heart Failure 2 (RELAX‐AHF‐2) trial. Methods and results: Patients enrolled in RELAX‐AHF‐2 with available data regarding MR status were included in this analysis. Baseline characteristics, in‐hospital data, and clinical outcomes through 180‐day follow‐up were evaluated. The impact of moderate/severe MR was assessed. Among 6420 AHF patients with known MR status, 1810 patients (28.2%) had moderate/severe MR. Compared to patients with no/mild MR, those with moderate/severe MR were more likely to have history of heart failure (HF), prior HF hospitalization, more comorbidities, symptoms/signs of HF, lower left ventricular ejection fraction and higher N‐terminal pro‐B‐type natriuretic peptide levels. Moderate/severe MR was associated with longer length of hospital stay, higher rates of residual dyspnoea, increased jugular venous pressure through the index hospitalization and a higher unadjusted risk of the composite of cardiovascular (CV) death or rehospitalization for HF/renal failure (RF) through 180 days (crude hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.03–1.27, p = 0.01). The association between moderate/severe MR and poorer outcomes was not maintained in a multivariable model including several covariates of interest (adjusted HR 1.03, 95% CI 0.91–1.17, p = 0.65). Similar findings were observed for HF/RF rehospitalization alone. Conclusions: In patients with AHF, moderate/severe MR was associated with a worse clinical profile but did not have an independent prognostic impact on clinical outcomes. [ABSTRACT FROM AUTHOR]

Aim: N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) is predictive of both outcomes and response to treatment in patients with heart failure with reduced ejection fraction (HFrEF). The aim of this study was to examine the effect of the cardiac myosin activator omecamtiv mecarbil according to baseline NT‐proBNP level in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure trial (GALACTIC‐HF). Methods and results: The primary outcome was the composite of a worsening heart failure event (urgent clinic visit, emergency department visit, or hospitalization) or cardiovascular death. We prespecified analysis of the effect of treatment according to baseline NT‐proBNP (≤ median, > median), excluding individuals with atrial fibrillation/flutter (AF/AFL). Of the 8232 patients analysed, 8206 had an available baseline NT‐proBNP measurement. Among the 5971 patients not in AF/AFL, the median (Q1–Q3) NT‐proBNP level was 1675 (812–3579) pg/ml. Hazard ratios (HR) for the effect of omecamtiv mecarbil, compared with placebo, for the primary endpoint in patients without AF/AFL were: ≤ median 0.94 (95% confidence interval [CI] 0.80–1.09), > median 0.81 (0.73–0.90) (p‐interaction = 0.095); for the overall population (including patients with AF/AFL) the HRs were ≤ median 1.01 (0.90–1.15) and > median 0.88 (0.80–0.96) (p‐interaction = 0.035). There was an interaction between treatment and NT‐proBNP, examined as a continuous variable, with greater effect of omecamtiv mecarbil on the primary outcome in patients with a higher baseline NT‐proBNP (p‐interaction = 0.086). Conclusions: In GALACTIC‐HF, the benefit of omecamtiv mecarbil appeared to be larger in patients with higher baseline NT‐proBNP levels, especially in patients without AF/AFL. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02929329; EudraCT number, 2016‐002299‐28. [ABSTRACT FROM AUTHOR]

Aim: Recent data suggest that guideline‐directed medical therapy of patients with heart failure (HF) with reduced ejection fraction (HFrEF) might improve clinical outcomes in patients with HF up to a left ventricular ejection fraction (LVEF) of 55–65%, whereas patients with higher LVEF do not seem to benefit. Recent data have shown that LVEF may have a U‐shaped relation with outcome, with poorer outcome also in patients with supranormal values. This suggests that patients with supranormal LVEF may be a distinctive group of patients. Methods and results: RELAX‐AHF‐2 was a multicentre, placebo‐controlled trial on the effects of serelaxin on 180‐day cardiovascular (CV) mortality and worsening HF at day 5 in patients with acute HF. Echocardiograms were performed at hospital admission in 6128 patients: 155 (2.5%) patients were classified as HF with supranormal ejection fraction (HFsnEF; LVEF >65%), 1440 (23.5%) as HF with preserved ejection fraction (HFpEF; LVEF 50–65%), 1353 (22.1%) as HF with mildly reduced ejection fraction (HFmrEF; LVEF 41–49%) and 3180 (51.9%) as HFrEF (LVEF <40%). Patients with HFsnEF compared to HFpEF were more often women, had higher prevalence of non‐ischaemic HF, had lower levels of natriuretic peptides, were less likely to be treated with beta‐blockers and had higher blood urea nitrogen plasma levels. All‐cause mortality was not statistically different between groups, although patients with HFsnEF had the highest numerical rate. A declining trend was seen in the proportion of 180‐day deaths due to CV causes from HFrEF (290/359, 80.8%) to HFsnEF (14/24, 58.3%). The reverse was observed with death from non‐CV causes. No treatment effect of serelaxin was observed in any of the subgroups. Conclusions: In this study, only 2.5% of patients were classified as HFsnEF. HFsnEF was primarily characterized by female sex, lower natriuretic peptides and a higher risk of non‐CV death. [ABSTRACT FROM AUTHOR]

Background For patients with acute heart failure (AHF), substantial diuresis after administration of loop diuretics is generally associated with better clinical outcomes but may cause creatinine to rise, suggesting renal function decline. We investigated the interaction between diuretic response and worsening renal function (WRF) on clinical outcomes in patients with AHF. Methods and results In two AHF cohorts (PROTECT, n =1698 and RELAX-AHF-2, n =5586 in current analysis), the prognostic impact of WRF (creatinine =0.3 mg/dl increase baseline--day 4; sensitivity analyses incorporated baseline renal function) by diuretic response (kg weight loss/40 mg furosemide equivalent baseline--day 4) was investigated with regard to (cardiovascular) death or cardiovascular/renal hospitalization using subpopulation treatment effect pattern plots (STEPP) and survival analyses. WRF occurred in 286 (16.8%) and 1031 (18.5%) patients in PROTECT and RELAX-AHF-2, respectively. Patients with WRF had higher left ventricular ejection fraction and lower estimated glomerular filtration rate at baseline (p <0.05), and received higher doses of loop diuretics and had a worse diuretic response (p <0.001). In patients with a poor diuretic response (=0.35 kg weight loss/40 mg furosemide equivalent as identified by STEPP), WRF was associated with higher risk of (cardiovascular) death or cardiovascular/renal hospitalization (p <0.001 both cohorts), but this was not the case for patients with a good diuretic response (p =0.900 both cohorts). Conclusion In two large cohorts of patients with AHF, WRF in the first 4 days was not associated with worse outcomes when patients had a good diuretic response. The occurrence of WRF in patients with AHF should therefore be considered in the context of diuretic response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ABSTRACT FROM AUTHOR]

Aims: N‐terminal pro‐b‐type natriuretic peptide (NT‐proBNP) values may be influenced by patient factors beyond the severity of illness, including atrial fibrillation (AF), renal dysfunction, or increased body mass index (BMI). We hypothesized that these factors may influence the achievement of NT‐proBNP targets and clinical outcomes. Methods: A total of 894 patients with heart failure with reduced ejection fraction were enrolled in The Guiding Evidence‐Based Therapy Using Biomarker Intensified Treatment trial. NT‐proBNP was analysed every 3 months. Results: Forty per cent of patients had AF, the median estimated glomerular filtration rate (eGFR) was 59 mL/min/1.73 m2 [interquartile range (IQR) 43–76], and median BMI was 29 kg/m2 (IQR 25–34). Patients with AF, eGFR < 60 mL/min/1.73 m2, or a BMI < 29 kg/m2 had a higher level of NT‐proBNP at randomization and over all study visits (all P values < 0.001). Over 18 months, the rate of change of NT‐proBNP was less for patients with AF (compared with those without AF, P = 0.037) and patients with an eGFR < 60 mL/min/1.73 m2 (compared with eGFR > 60 mL/min/1.73 m2, P < 0.001). The rate of change of NT‐proBNP was similar for patients with a BMI above or below the median value. Using the 90 day NT‐proBNP, patients with AF, lower eGFR, or lower BMI were less likely to achieve the target NT‐proBNP < 1000 pg/mL than patients without AF, higher eGFR, or higher BMI, respectively. None of these differed between the Usual Care or Guided Care arm for AF, eGFR, or BMI (Pinteractions all NS). Conclusions: Patients with AF, a lower BMI, or worse renal function are less likely to achieve a lower or target NT‐proBNP. Clinicians should be aware of these factors both when interpreting NT‐proBNP levels and making therapeutic decisions about heart failure therapies. [ABSTRACT FROM AUTHOR]

Aims: Associations between growth differentiation factor‐15 (GDF‐15), cardiovascular outcomes, and exercise capacity among patients with a recent hospitalization for heart failure (HHF) and heart failure with reduced ejection fraction (HFrEF) are unknown. We utilized data from the 'Functional Impact of GLP‐1 for Heart Failure Treatment' (FIGHT) study to address these knowledge gaps. Methods and results: FIGHT was a randomized clinical trial testing the effect of liraglutide (vs. placebo) among 300 participants with HFrEF and a recent HHF. Multivariable regression models evaluated associations between baseline GDF‐15 and change in GDF‐15 (per 1000 pg/mL increase from baseline to 30 days) with clinical outcomes (at 180 days) and declines in exercise capacity (6 min walk distance ≥ 45 m). At baseline (n = 249), median GDF‐15 value was 3221 pg/mL (interquartile range 1938–5511 pg/mL). Participants in the highest tertile of baseline GDF‐15 were more likely to be male and have more co‐morbidities. After adjustment, an increase in GDF‐15 over 30 days was associated with higher risk of death or HHF [hazard ratio 1.35, 95% confidence interval (CI) 1.11–1.64]. In addition, higher baseline GDF‐15 (per 1000 pg/mL until 6000 pg/mL) and an increase in GDF‐15 over 30 days were associated with declining 6 min walk distance (odds ratio 1.26, 95% CI 1.02–1.55 and odds ratio 1.37, 95% CI 1.12–1.69, respectively). GDF‐15 levels remained stable among participants randomized to liraglutide. Conclusions: An increase in GDF‐15 over 30 days among patients in HFrEF was independently associated with an increased risk of cardiovascular events and declining exercise capacity. These results support the value of longitudinal GDF‐15 trajectory in informing risk of heart failure disease progression. [ABSTRACT FROM AUTHOR]

Volume recruitment from the splanchnic compartment is an important physiological response to stressors such as physical activity and blood loss. In the setting of heart failure (HF), excess fluid redistribution from this compartment leads to increased cardiac filling pressures with limitation in exercise capacity. Recent evidence suggests that blocking neural activity of the greater splanchnic nerve (GSN) could have significant benefits in some patients with HF by reducing cardiac filling pressures and improving exercise capacity. However, to date the long‐term safety of splanchnic nerve modulation (SNM) in the setting of HF is unknown. SNM is currently used in clinical practice to alleviate some forms of chronic abdominal pain. A systematic review of the series where permanent SNM was used as a treatment for chronic abdominal pain indicates that permanent SNM is well tolerated, with side‐effects limited to transient diarrhoea or abdominal colic and transient hypotension. The pathophysiological role of the GSN in volume redistribution, the encouraging findings of acute and chronic pilot SNM studies and the safety profile from permanent SNM for pain provides a strong basis for continued efforts to study this therapeutic target in HF. [ABSTRACT FROM AUTHOR]

In addition, the RV-ESA and PASP together with parameters of RV-PA coupling (TAPSE/PASP ratio and RVOT-VTI/PASP ratio) improved significantly in the PK-titration group as compared to the placebo group ( I Table i 1 and I Figure i 1). Our analyses demonstrated that 20 weeks of OM treatment in patients with HFrEF improved RV-SET, RV-VTI in both OM groups, and improved RV-ESA, RV afterload and RV-PA coupling only in the PK-titration group, whereas OM did not significantly improve TAPSE or RV-FAC. Right ventricular (RV) dysfunction due to post-capillary pulmonary hypertension is a common sequela of elevated left ventricular (LV) filling pressures in patients with heart failure (HF) which has been demonstrated to be associated with poor clinical outcomes.1-3 Measures of RV-pulmonary artery (RV-PA) coupling that evaluate indices of RV function and pulmonary hypertension severity have been shown to be associated with clinical outcomes.4,5 A phase 2 trial, COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure, NCT01786512) demonstrated that treatment with omecamtiv mecarbil (OM), a selective cardiac myosin activator, known as a myotrope, was related to an improved LV systolic function, beneficial reverse remodelling, sympathetic withdrawal and a reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients with HF with reduced ejection fraction (HFrEF).6 In this research letter, we report the treatment effect of OM on RV structure and function together with RV-PA coupling in patients with HFrEF. [Extracted from the article]

In this document, we propose a universal definition of heart failure (HF) as a clinical syndrome with symptoms and/or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion. We also propose revised stages of HF as: At risk for HF (Stage A), Pre‐HF (Stage B), Symptomatic HF (Stage C) and Advanced HF (Stage D). Finally, we propose a new and revised classification of HF according to left ventricular ejection fraction (LVEF). This includes HF with reduced ejection fraction (HFrEF): symptomatic HF with LVEF ≤40%; HF with mildly reduced ejection fraction (HFmrEF): symptomatic HF with LVEF 41–49%; HF with preserved ejection fraction (HFpEF): symptomatic HF with LVEF ≥50%; and HF with improved ejection fraction (HFimpEF): symptomatic HF with a baseline LVEF ≤40%, a ≥10 point increase from baseline LVEF, and a second measurement of LVEF > 40%. [ABSTRACT FROM AUTHOR]

Aims: Whether risk of worsening renal function (WRF) during acute heart failure (AHF) hospitalization or the association between in‐hospital WRF and post‐discharge outcomes vary according to left ventricular ejection fraction (LVEF) is uncertain. We assessed incidence of WRF, factors related to its development and impact of WRF on post‐discharge outcomes across the spectrum of LVEF in patients enrolled in RELAX‐AHF‐2. Methods and results: A total of 6112 patients who had LVEF measured on admission and renal function determined prospectively during hospitalization were included. WRF, defined as a rise in serum creatinine ≥0.3 mg/dL from baseline through day 5, occurred in 1722 patients (28.2%). Incidence increased progressively from lowest to highest LVEF quartile (P < 0.001). After baseline adjustment, WRF risk in Q4 (LVEF >50%) remained significantly greater than in Q1 (LVEF ≤29%; hazard ratio 1.2, 95% confidence interval 1–1.43; P = 0.050). Age and comorbidity burden including chronic kidney disease increased as LVEF increased. Neither admission haemodynamic abnormalities, extent of diuresis during hospitalization nor residual congestion explained the increased incidence of WRF in patients with higher LVEF. Serelaxin treatment and diuretic responsiveness were associated with reduced risk of WRF in all LVEF quartiles. WRF in patients in the upper three LVEF quartiles increased risk of post‐discharge events. Conclusions: Worsening renal function incidence during AHF hospitalization increases progressively with LVEF. Greater susceptibility of patients with higher LVEF to WRF appears more related to their advanced age and worse underlying kidney function rather than haemodynamic or treatment effects. WRF is associated with increased risk of post‐discharge events except in patients in the lowest LVEF quartile. [ABSTRACT FROM AUTHOR]

Aims: We sought to determine sex‐based differences in biomarkers, self‐reported health status, and magnitude of longitudinal changes in measures of reverse cardiac remodelling among patients with heart failure with reduced ejection fraction (HFrEF, left ventricular ejection fraction ≤40%) treated with sacubitril/valsartan (S/V). Methods and results: This was a subgroup analysis of patients initiated on S/V in the Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure (PROVE‐HF) study. There were 226 (28.5%) women in the study. Though women had lower baseline N‐terminal pro B‐type natriuretic peptide (NT‐proBNP), they had more rapid early reduction in the biomarker after initiation of S/V. Compared to men, women had lower average baseline Kansas City Cardiomyopathy Questionnaire (KCCQ)‐23 Total Symptom score (67.6 vs. 71.9; P = 0.003) but showed greater linear improvement (7.4 vs. 5.5 points; P < 0.001) and faster pace of KCCQ change (P < 0.001) over the course of the trial. Women and men demonstrated similar degrees of reverse left ventricular remodelling following S/V initiation; however, women did so earlier than men with more consistent changes. These results remained unchanged with adjustment for relevant covariates. Reduction in NT‐proBNP was associated with reverse cardiac remodelling in both women and men. Treatment with S/V was well tolerated in all. Conclusions: In women with HFrEF, treatment with S/V was associated with significant NT‐proBNP reduction, health status improvement and reverse cardiac remodelling. [ABSTRACT FROM AUTHOR]

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and results: Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N‐terminal pro‐B‐type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC‐HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m2 (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation. [ABSTRACT FROM AUTHOR]

The role of obesity in the pathogenesis of heart failure (HF), and in particular HF with preserved ejection fraction (HFpEF), has drawn significant attention in recent years. The prevalence of both obesity and HFpEF has increased worldwide over the past decades and when present concomitantly suggests an obese‐HFpEF phenotype. Anthropometrics, including body mass index, waist circumference, and waist‐to‐hip ratio, are associated with incident HFpEF. However, the cardiovascular effects of obesity may actually be driven by the distribution of fat, which can accumulate in the epicardial, visceral, and subcutaneous compartments. Regional fat can be quantified using non‐invasive imaging techniques, including computed tomography, magnetic resonance imaging, and dual‐energy X‐ray absorptiometry. Regional variations in fat accumulation are associated with different HFpEF risk profiles, whereby higher epicardial and visceral fat have a much stronger association with HFpEF risk compared with elevated subcutaneous fat. Thus, regional adiposity may serve a pivotal role in the pathophysiology of HFpEF contributing to decreased cardiopulmonary fitness, impaired left ventricular compliance, upregulation of local and systemic inflammation, promotion of neurohormonal dysregulation, and increased intra‐abdominal pressure and vascular congestion. Strategies to reduce total and regional adiposity have shown promise, including intensive exercise, dieting, and bariatric surgery programmes, but few studies have focused on HFpEF‐related outcomes among obese. Further understanding the role these variable fat depots play in the progression of HFpEF and HFpEF‐related hospitalizations may provide therapeutic targets in treating the obese‐HFpEF phenotype. [ABSTRACT FROM AUTHOR]

Aim: Istaroxime is a first‐in‐class agent which acts through inhibition of the sarcolemmal Na+/K+ pump and activation of the SERCA2a pump. This study assessed the effects of a 24 h infusion of istaroxime in patients hospitalised for acute heart failure (AHF). Methods and results: We included patients hospitalised for AHF with left ventricular ejection fraction ≤40% and E/e' > 10. Patients were randomised to a 24 h intravenous infusion of placebo or istaroxime at doses of 0.5 μg/kg/min (cohort 1: placebo n = 19; istaroxime n = 41) or 1.0 μg/kg/min (cohort 2: placebo n = 20, istaroxime n = 40). The primary endpoint of change in E/e' ratio from baseline to 24 h decreased with istaroxime vs. placebo (cohort 1: −4.55 ± 4.75 istaroxime 0.5 μg/kg/min vs. −1.55 ± 4.11 placebo, P = 0.029; cohort 2: −3.16 ± 2.59 istaroxime 1.0 μg/kg/min vs. −1.08 ± 2.72 placebo, P = 0.009). Both istaroxime doses significantly increased stroke volume index and decreased heart rate. Systolic blood pressure increased with istaroxime, achieving significance with the high dose. Self‐reported dyspnoea and N‐terminal pro‐brain natriuretic peptide improved in all groups without significant differences between istaroxime and placebo. No significant differences in cardiac troponin absolute values or clinically relevant arrhythmias were observed during or after istaroxime infusion. Serious cardiac adverse events (including arrhythmias and hypotension) did not differ between placebo and istaroxime groups. The most common adverse events were injection site reactions and gastrointestinal events, the latter primarily with istaroxime 1.0 μg/kg/min. Conclusions: In patients hospitalised for AHF with reduced ejection fraction, a 24 h infusion of istaroxime improved parameters of diastolic and systolic cardiac function without major cardiac adverse effects. [ABSTRACT FROM AUTHOR]

Aims: Although left ventricular ejection fraction (LVEF) is routinely used to categorize patients with heart failure (HF), whether it predicts outcomes after hospitalization for acute heart failure (AHF) is uncertain. Consequently, we assessed the relationship between LVEF and cardiovascular (CV) outcomes in a large, well characterized cohort of patients hospitalized for AHF.Methods and Results: The 6128 patients from the RELAX-AHF-2 trial who had LVEF measured during AHF hospitalization were separated into LVEF quartiles and the relationship between LVEF and a composite of CV mortality and rehospitalization for HF or renal failure through 180 days was assessed. We found progressively lower risk for this composite outcome as LVEF increased (hazard ratio 0.95, 95% confidence interval 0.93-0.98 per 5% LVEF increase, P < 0.001) that was driven predominantly by decreased risk for rehospitalization. The smoothed spline curve depicting risk remained stable as LVEF decreased until reaching approximately 40%, at which point risk increased progressively with further reductions in LVEF. Significant differences between LVEF quartiles for post-discharge CV risk were seen in patients with an ischaemic aetiology or with a history of HF preceding index hospitalization, but were less robust in patients with non-ischaemic aetiology and absent in those with de novo HF.Conclusion: In patients hospitalized with AHF, CV events over 180 days were more frequent in patients with lower LVEF. This was due predominantly to a significant increase in risk for HF/renal failure rehospitalization but not in either CV or all-cause mortality. LVEF had greater prognostic value in patients with ischaemic aetiology or pre-existing HF. [ABSTRACT FROM AUTHOR]

Aims: The effectiveness and safety of 48 h intravenous 30 μg/kg/day serelaxin infusion in acute heart failure (AHF) has been studied in six randomized, controlled clinical trials.Methods and Results: We conducted a fixed-effect meta-analysis including all studies of intravenous serelaxin initiated within the first 16 h of admission for AHF. Endpoints considered were the primary and secondary endpoints examined in the serelaxin phase III studies. In six randomized controlled trials, 6105 total patients were randomized to receive intravenous serelaxin 30 μg/kg/day and 5254 patients to control. Worsening heart failure to day 5 occurred in 6.0% and 8.1% of patients randomized to serelaxin and control, respectively (hazard ratio 0.77, 95% confidence interval 0.67-0.89; P = 0.0002). Serelaxin had no statistically significant effect on length of stay, or cardiovascular death, or heart or renal failure rehospitalization. Serelaxin administration resulted in statistically significant improvement in markers of renal function and reductions in both N-terminal pro-B-type natriuretic peptide and troponin. No significant adverse outcomes were noted with serelaxin. Through the last follow-up, which occurred at an average of 4.5 months (1-6 months), serelaxin administration was associated with a reduction in all-cause mortality, with an estimated hazard ratio of 0.87 (95% confidence interval 0.77-0.98; P = 0.0261).Conclusions: Administration of intravenous serelaxin to patients admitted for AHF was associated with a highly significant reduction in the risk of 5-day worsening heart failure and in changes in renal function markers, but not length of stay, or cardiovascular death, or heart or renal failure rehospitalization. Serelaxin administration was safe and associated with a significant reduction in all-cause mortality. [ABSTRACT FROM AUTHOR]

A study published in the European Journal of Heart Failure examined the use of vasodilators in patients with heart failure. The study found that while vasodilators can lower peripheral resistance and increase cardiac output, they may impair diuresis and have little benefit for patients with heart failure who are congested. Observational studies suggest that vasodilators may improve hemodynamics and preserve renal function in patients with acute heart failure, but randomized trials have not shown any clinical benefit. The authors recommend avoiding the use of vasodilators in patients with acute heart failure unless there is a specific reason for their use, and instead focusing on guideline-recommended medical therapy. [Extracted from the article]

Aims: Neurohormonal activation characterizes chronic heart failure (HF) and is a well-established therapeutic target. Neurohormonal activation may also play a key role in acute HF (AHF). We aim to describe the association between plasma renin activity (PRA) and three AHF outcomes: (i) worsening HF or death through day 5 of hospitalization; (ii) HF rehospitalization or death through day 30; and (iii) all-cause death through day 30.Methods and Results: A secondary analysis of the BLAST-AHF trial was performed. Eligible patients had a history of HF, elevated natriuretic peptides, signs and symptoms of HF, systolic blood pressure >120 mmHg, and an estimated glomerular filtration rate between 20-75 mL/min/1.73 m2 . The primary trial was neutral, with no differential effect of study drug by PRA levels. Baseline PRA levels were grouped into tertiles. Adjusted Cox proportional hazard model determined the association of PRA levels with outcomes (α set at P < 0.05). Of 618 randomized patients, 578 (93.5%) had a baseline PRA. PRA was modestly, but significantly, associated with each outcome without adjustment [worsening HF or death through day 5: hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.01-1.23, P = 0.04; HF rehospitalization or death through day 30: HR 1.13, 95% CI 1.02-1.26, P = 0.02; all-cause death through day 30: HR 1.18, 95% CI 1.02-1.37, P = 0.03]. After multivariable adjustment, PRA was only significantly associated with HF rehospitalization or death through day 30 (HR 1.15, 95% CI 1.01-1.32, P = 0.04).Conclusion: Baseline PRA levels are associated with increased risk for the composite of 30-day HF rehospitalization or death in patients with AHF. [ABSTRACT FROM AUTHOR]

Aims: Episodes of acute heart failure (AHF) may lead to end‐organ dysfunction. In this post hoc analysis of the Relaxin in Acute Heart Failure trial, we used the MELD‐XI (Model of End‐Stage Liver Dysfunction) score to examine hepatorenal dysfunction in patients with AHF. Methods and results: On admission, the MELD‐XI score was elevated (abnormal) in 918 (82%) patients, with 638 (57%) having isolated renal dysfunction (creatinine > 1 mg/dL), 73 (6.5%) isolated liver dysfunction (bilirubin > 1 mg/dL), and 207 (18.5%) coexisting dysfunction of the kidneys and the liver (both creatinine and bilirubin > 1 mg/dL). The percentage of patients with elevated MELD‐XI score remained constant through a 60 day follow‐up, as we observed a gradual decrease of liver dysfunction prevalence, counterbalanced by an increase in renal dysfunction. Serelaxin treatment was associated with a lower MELD‐XI score on Day 2 and Day 5 (both P < 0.05), but this difference vs. placebo disappeared during longer follow‐up. In the multivariable model, an elevated MELD‐XI score on admission was associated with higher 180 day mortality: hazard ratios (95% confidence interval) for cardiovascular death were 3.10 (1.22–7.87), and for all‐cause death 2.47 (1.19–5.15); both P < 0.05. The addition of the MELD‐XI score to a prespecified prognostic model increased the discrimination of the model for all‐cause death, but the increment in the C‐index was only modest: 0.013 (P = 0.02). Conclusions: In patients with AHF, hepatorenal dysfunction is prevalent and related to poor outcome. The MELD‐XI score is a useful prognosticator in AHF. [ABSTRACT FROM AUTHOR]

Hospitalisation for acute heart failure remains a major public health problem with high prevalence, morbidity, mortality, and cost. Prior attempts to develop new therapies for this condition have not been successful. Nitroxyl (HNO) plays a unique role in cardiovascular physiology by direct post-translational modification of thiol residues on target proteins, specifically SERCA2a, phospholamban, the ryanodine receptor and myofilament proteins in cardiomyocytes. In animal models, these biological effects lead to vasodilatation, increased inotropy and lusitropy, but without tachyphylaxis, pro-arrhythmia or evidence of increased myocardial oxygen demand. BMS-986231 is an HNO donor being developed as a therapy for heart failure, and initial studies in patients with heart failure support the potential clinical value of these physiological effects. In this manuscript, we describe the ongoing phase II development programme for BMS-986231, which consists of three related randomised placebo-controlled clinical trials, StandUP-AHF, StandUP-Imaging and StandUP-Kidney, which are designed to provide evidence of tolerability and efficacy as well as confirm the anticipated physiological effects in patients with heart failure with reduced ejection fraction. These studies will set the stage for the further study of BMS-986231 in future phase III clinical trials. [ABSTRACT FROM AUTHOR]

Background: Most heart failure (HF) risk scores have been derived from cohorts of stable HF patients and may not incorporate up to date treatment regimens or deep phenotype characterization that change baseline risk over the short- and long-term follow-up period. We undertook the current analysis of participants in the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment) trial to address these limitations.Methods and Results: The GUIDE-IT study randomized 894 high-risk patients with HF and reduced ejection fraction (≤ 40%) to biomarker-guided treatment strategy vs. usual care. We performed risk modelling using Cox proportional hazards models and analysed the relationship between 35 baseline clinical factors and the primary composite endpoint of cardiovascular (CV) death or HF hospitalization, the secondary endpoint of all-cause mortality, and the exploratory endpoint of 90-day HF hospitalization or death. Prognostic relationships for continuous variables were examined and key predictors were identified using a backward variable selection process. Predictive models and risk scores were developed. Over a median follow-up of 15 months, the cumulative number of HF hospitalizations and CV deaths was 328 out of 894 patients (Kaplan-Meier event rate 34.5% at 12 months). Frequency of all-cause deaths was 143 out of 894 patients (Kaplan-Meier event rate 12.2% at 12 months). Outcomes for the primary and secondary endpoints between strategy arms of the study were similar. The most important predictor that was present in all three models was the baseline natriuretic peptide level. Hispanic ethnicity, low sodium and high heart rate were present in two of the three models. Other important predictors included the presence or absence of a device, New York Heart Association class, HF duration, black race, co-morbidities (sleep apnoea, elevated creatinine, ischaemic heart disease), low blood pressure, and a high congestion score.Conclusion: Risk models using readily available clinical information are able to accurately predict short- and long-term CV events and may be useful in optimizing care and enriching patients for clinical trials.Clinical Trial Registration: ClinicalTrials.gov ID number NCT01685840. [ABSTRACT FROM AUTHOR]

Aim: There is limited information on the outcomes after primary prevention implantable cardioverter-defibrillator (ICD) implantation in patients with heart failure (HF) and diabetes. This analysis evaluates the effectiveness of a strategy of ICD plus medical therapy vs. medical therapy alone among patients with HF and diabetes.Methods and Results: A patient-level combined-analysis was conducted from a combined dataset that included four primary prevention ICD trials of patients with HF or severely reduced ejection fractions: Multicenter Automatic Defibrillator Implantation Trial I (MADIT I), MADIT II, Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE), and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). In total, 3359 patients were included in the analysis. The primary outcome of interest was all-cause death. Compared with patients without diabetes (n = 2363), patients with diabetes (n = 996) were older and had a higher burden of cardiovascular risk factors. During a median follow-up of 2.6 years, 437 patients without diabetes died (178 with ICD vs. 259 without) and 280 patients with diabetes died (128 with ICD vs. 152 without). ICDs were associated with a reduced risk of all-cause mortality among patients without diabetes [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46-0.67] but not among patients with diabetes (HR 0.88, 95% CI 0.7-1.12; interaction P = 0.015).Conclusion: Among patients with HF and diabetes, primary prevention ICD in combination with medical therapy vs. medical therapy alone was not significantly associated with a reduced risk of all-cause death. Further studies are needed to evaluate the effectiveness of ICDs among patients with diabetes. [ABSTRACT FROM AUTHOR]

Aims Patients hospitalized for heart failure (HF) are at high risk for 30-day readmission. This study sought to examine the timings and causes of readmission within 30 days of an HF hospitalization. Methods and results Timing and cause of readmission in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial were assessed. Early and late readmissions were defined as admissions occurring within 0-7 days and 8-30 days post-discharge, respectively. Patients who died in hospital or remained hospitalized at day 30 post-randomization were excluded. Patients were compared by timing and cause of readmission. Logistic and Cox proportional hazards regression analyses were used to identify independent risk factors for early vs. late readmission and associations with 180-day outcomes. Of the 6584 patients (92%) in the ASCEND-HF population included in this analysis, 751 patients (11%) were readmitted within 30 days for any cause. Overall, 54% of readmissions were for non-HF causes. The median time to rehospitalization was 11 days (interquartile range: 6-18 days) and 33% of rehospitalizations occurred by day 7. Rehospitalization within 30 days was independently associated with increased risk for 180-day all-cause death [hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.93-2.94; P <0.001]. Risk for 180-day all-cause death did not differ according to early vs. late readmission (HR 0.99, 95% CI 0.67-1.45; P =0.94). Conclusions In this hospitalized HF trial population, a significant majority of 30-day readmissions were for non-HF causes and one-third of readmissions occurred in the first 7 days. Early and late readmissions within the 30-day timeframe were associated with similarly increased risk for death. Continued efforts to optimize multidisciplinary transitional care are warranted to improve rates of early readmission. [ABSTRACT FROM AUTHOR]

B This article refers to 'Association of time-to-intravenous furosemide with mortality in acute heart failure: data from REPORT-HF' by W. Ouwerkerk I et al i ., published in this issue on pages 43-51. b There are acute cardiovascular conditions in which the speed of treatment is directly correlated with clinical outcomes - most notably, in ST-elevation myocardial infarction ("door-to-balloon time") and in cardiac arrest (time to defibrillation). Early intravenous heart failure therapy and outcomes among older patients hospitalized for acute decompensated heart failure: findings from the Acute Decompensated Heart Failure Registry Emergency Module (ADHERE-EM). Patients in whom an AHF diagnosis is more apparent (thus allowing for prompter treatment) may have an inherently more favourable long-term prognosis than patients with greater diagnostic complexity (resulting in delayed first diuretic doses). [Extracted from the article]

Abstract: Each year over one million patients with acute heart failure (AHF) present to a United States emergency department (ED). The vast majority are hospitalized for further management. The length of stay and high postdischarge event rate in this cohort have changed little over the past decade. Therapeutic trials have failed to yield substantive improvement in postdischarge outcomes; subsequently, AHF care has changed little in the past 40 years. Prior research studies have been fragmented as either “inpatient” or “ED‐based.” Recognizing the challenges in identification and enrollment of ED patients with AHF, and the lack of robust evidence to guide management, an AHF clinical trials network was developed. This network has demonstrated, through organized collaboration between cardiology and emergency medicine, that many of the hurdles in AHF research can be overcome. The development of a network that supports the collaboration of acute care and HF researchers, combined with the availability of federally funded infrastructure, will facilitate more efficient conduct of both explanatory and pragmatic trials in AHF. Yet many important questions remain, and in this document our group of emergency medicine and cardiology investigators have identified four high‐priority research areas. [ABSTRACT FROM AUTHOR]

Aims: We evaluated the added prognostic value of a multi-time point-based multimarker panel of biomarkers in patients with acute heart failure (AHF).Methods and Results: Seven circulating biomarkers [NT-proBNP, high sensitivity cardiac troponin T (hs-cTnT), soluble ST2 (sST2), growth differentiation factor 15 (GDF-15), cystatin-C, galectin-3, and high sensitivity C-reactive protein (hs-CRP)] were measured at baseline and on days 2, 5, 14, and 60 in 1161 patients enrolled in the RELAX-AHF trial. Patients with BNP ≥350 ng/L or NT-proBNP ≥1400 ng/L, mild to moderate renal impairment, and systolic blood pressure >125 mmHg were included in the trial. Time-dependent Cox regression analysis was utilized to evaluate the incremental value of serial measurement of biomarkers. Added value of individual biomarkers and their combination, on top of a pre-specified baseline model, was quantified with the gain in the C-index. Serial biomarker evaluation showed incremental predictive value over baseline measurements alone for the prediction of 180-day cardiovascular mortality except for galectin-3. While a repeat measurement as early as day 2 was adequate for NT-proBNP and cystatin-C in terms of maximizing discriminatory accuracy, further measurements on days 14 and 60 provided added value for hs-cTnT, GDF-15, sST2, and hs-CRP. Individual biomarker additions on top of the baseline model showed additional prognostic value. The greatest prognostic gain was, however, attained with the combination of NT-proBNP, hs-cTnT, GDF-15, and sST2, which yielded 0.08 unit absolute increment in the C-index to 0.87 (95% confidence interval 0.83-0.91].Conclusion: In patients with AHF and mild to moderate renal impairment, a multimarker approach based on a panel of serially evaluated biomarkers provides the greatest prognostic improvement unmatched by a single time point-based single marker strategy. [ABSTRACT FROM AUTHOR]